The primary cilium as a signaling center in neural circuit development

Cilium
Cilium

Our work on the role of morphogens in axon guidance has identified a dual role of Shh (Sonic hedgehog) in the navigation of post-crossing commissural axons. Shh has a direct effect on the navigation of post-crossing axons expressing Hhip as a receptor. Hhip mediates a repulsive effect resulting in axons turning away from high concentration of Shh. In addition, Shh guides post-crossing commissural axons indirectly by shaping a Wnt gradient with opposite orientation compared to the Shh gradient. Wnt acts as attractant for post-crossing axons. Wnt signaling in commissural axon guidance is complex and uses components of both the canonical (β-Catenin-dependent) and the planar cell polarity pathway. Detailed analysis of Shh signaling in post-crossing commissural axons suggests that the primary cilium is required in a cell-autonomous manner in both mouse and chicken embryos.

 

OB
OB

In mouse, an effect of primary cilium-mediated signaling on cell differentiation and axon guidance cannot be separated. However, our studies in chicken embryos with the possibility for precise temporal control of loss of gene function demonstrated that the primary cilium is directly involved in axon guidance. In collaboration with pediatricians and human geneticists, we have generated an animal model to study the effect of mutations in C5ORF42/Jbts17, a ciliary gene. Patients suffer from intellectual disability and exhibit facial dysmorphology. These findings are in line with the animal model, where facial structures were found to be aberrant and neural circuit formation was compromised.